AYVAKYT

1). Posology for GIST Patient selection for treatment of unresectable or metastatic GIST harbouring the PDGFRA D842V mutation should be based on a validated test method. The recommended starting dose of avapritinib is 300 mg orally once daily, on an empty stomach (see Method of administration).

The dose should be adjusted based on safety and tolerability. Treatment should be continued until disease progression or unacceptable toxicity. Concomitant use of avapritinib with strong or moderate CYP3A inhibitors should be avoided.

5). Posology for AdvSM The recommended starting dose of avapritinib is 200 mg orally once daily, on an empty stomach (see Method of administration). This once daily 200 mg dose is also the maximum recommended dose. Continue treatment until SM disease progression or unacceptable toxicity.

4). Concomitant use of avapritinib with strong or moderate CYP3A inhibitors should be avoided. 5). Dose modifications for adverse reactions Irrespective of indication, interruption of treatment with or without dose reduction may be considered to manage adverse reactions based on severity and clinical presentation.

The dose should be adjusted as recommended, based on safety and tolerability. Dose reductions and modifications for adverse reactions are recommended in patients with GIST and AdvSM and are provided in Tables 1 and 2. Table 1. Recommended dose reductions for AYVAKYT for adverse reactions Dose reduction GIST (starting dose 300 mg) AdvSM (starting dose 200 mg) First 200 mg once daily 100 mg once daily Second 100 mg once daily 50 mg once daily Third - 25 mg once daily Table 2.

4) All Grades Permanently discontinue AYVAKYT. Grade 1 Continue at the same dose, reduce dose or interrupt until improvement to baseline or resolution. Resume at the same dose or at a reduced dose. Grade 2 or Grade 3 Interrupt therapy until improved to baseline, Grade 1, or resolution.

Resume at the same dose or at a reduced dose. 4) Grade 4 Permanently discontinue AYVAKYT. 8) Grade 3 or Grade 4 Interrupt therapy until less than or equal to Grade 2. Resume at the same dose or at a reduced dose, if warranted. 4) Less than 50 x 109/L Interrupt dosing until platelet count is ≥ 50 x 109/L, then resume at reduced dose (see Table 1).

If platelet count does not recover above 50 x 109/L, consider platelet support. 0 ** Adverse reactions with impact on Activities of Daily Living (ADLs) for Grade 2 or higher adverse reactions Missed doses If a dose of avapritinib is missed, the patient should make up for the missed dose unless the next scheduled dose is within 8 hours (see Method of administration).

1. Unresectable or metastatic GIST The most common adverse reactions of any grade during treatment with avapritinib at a starting dose of 300 mg or 400 mg were nausea (45%), fatigue (40%), anaemia (39%), periorbital oedema (33%), face oedema (27%), hyperbilirubinaemia (28%), diarrhoea (26%), vomiting (24%), oedema peripheral (23%), lacrimation increased (22%), decreased appetite (21%) and memory impairment (20%).

Serious adverse reactions occurred in 23% of patients receiving avapritinib. The most common serious adverse reactions during treatment with avapritinib were anaemia (6%), and pleural effusion (1%). The most common adverse reactions leading to permanent treatment discontinuation were fatigue, encephalopathy and intracranial haemorrhage (< 1% each).

Adverse reactions leading to a dose reduction included anaemia, fatigue, neutrophil count decreased, blood bilirubin increased, memory impairment, cognitive disorder, periorbital oedema, nausea and face oedema. Advanced systemic mastocytosis The most common adverse reactions of any grade during treatment with avapritinib at a starting dose of 200 mg were periorbital oedema (38%), thrombocytopenia (37%), oedema peripheral (33%), and anaemia (22%).

Serious adverse reactions occurred in 12% of patients receiving avapritinib. The most common serious adverse reactions during treatment with avapritinib were subdural haematoma (2%), anaemia (2%), and haemorrhage (2%). 1% had adverse reactions leading to permanent treatment discontinuation.

6%), subdural haematoma occurred. 8% each). Adverse reactions leading to a dose reduction included thrombocytopenia, neutropenia, periorbital oedema, cognitive disorder, oedema peripheral, platelet count decreased, neutrophil count decreased, anaemia, asthenia, fatigue, arthralgia, blood alkaline phosphatase increased, blood bilirubin increased, and white blood cell count decreased.

Haemorrhages Avapritinib has been associated with an increased incidence of haemorrhagic adverse reactions, including serious and severe adverse reactions, like gastrointestinal haemorrhage and intracranial haemorrhage, in patients with unresectable or metastatic GIST and AdvSM.

8). g. warfarin, phenprocoumon, rivaroxaban, dabigatran, apixaban and edoxaban) or other concomitant medicinal products that increase the risk of bleeding (including antiplatelet therapy). 8). Fatal events have occurred in <1% of patients across all doses.

The exact mechanism is unknown. Before initiating avapritinib at any dose the risk for intracranial haemorrhage should be carefully considered in patients with risk factors such as concomitant use of anticoagulants, severe thrombocytopenia, a history of vascular aneurysm intracranial haemorrhage, cerebrovascular accident or transient ischaemic attack within the prior year.

g. severe headache, vision problems, somnolence, or focal weakness) during treatment with avapritinib should interrupt treatment and inform their healthcare professional immediately. Brain imaging by magnetic resonance imaging (MRI) or computed tomography (CT) may be performed at the discretion of the physician based on severity and the clinical presentation.

2). 8). There is no clinical study experience using avapritinib in patients with brain metastases. 8). Fatal events have occurred in <1% of patients. The incidence of intracranial haemorrhage was higher in patients with platelet counts <50 x 109/L and in patients with a starting dose of ≥300 mg.

Considering the above, a platelet count must be performed prior to initiating therapy. Avapritinib is not recommended in patients with platelet counts <50 x 109/L. Following treatment initiation, platelet counts must be performed every 2 weeks for the first 8 weeks regardless of baseline platelet count.

1.